Methods of modulating angiogenesis

Abstract

Featured are methods of modulating angiogenesis, e.g., by modulating PKC delta. The methods are useful in the treatment of disorders characterized by aberrant and/or increased blood vessel formation and/or increased permeability. The methods are also useful for treatment a disorder characterized by abnormal, inadequate or unstable blood vessel formation or increased permeability. Also featured are diagnostic and screening methods.

What is claimed is:  
     
         1 . A method of modulating angiogenesis in a cell, tissue, or subject, comprising modulating a PKC delta.  
     
     
         2 . The method of  claim 1 , wherein angiogenesis is inhibited by administering an inhibitor of PKC delta to the cell, tissue or subject.  
     
     
         3 . The method of  claim 2 , wherein the inhibitor of PKC delta is Rottlerin.  
     
     
         4 . The method of  claim 2 , wherein the inhibitor of PKC delta is selected from the group of: an inhibitory PKC delta antibody, a PKC delta antisense nucleic acid, an inhibitory PKC delta binding peptide, and an inhibitory PKC delta binding small molecule.  
     
     
         5 . The method of  claim 2 , wherein the subject has or is at risk for a disorder characterized by aberrant and/or increased blood vessel formation and/or increased permeability.  
     
     
         6 . The method of  claim 5 , wherein the disorder is tumor metastasis.  
     
     
         7 . The method of  claim 1 , wherein angiogenesis is promoted by administering an agonist of PKC delta to the cell, tissue or subject.  
     
     
         8 . The method of  claim 9 , wherein the PKC delta agonist is selected from the group of: PKC delta polypeptide or functional fragment or analog thereof; a nucleic acid sequence encoding a PKC delta polypeptide or a functional fragment or analog thereof; and an agent which increases PKC delta expression.  
     
     
         9 . The method of  claim 7 , wherein the subject has a disorder characterized by abnormal, inadequate or unstable blood vessel formation.  
     
     
         10 . The method of  claim 7 , wherein the subject has a disorder characterized by increased permeability.  
     
     
         11 . A method of determining if a subject is at risk for a disorder characterized by abnormal or inadequate blood vessel formation, comprising: 
 detecting, the presence or absence of a genetic lesion in a PKC delta gene, wherein the presence of a genetic lesion in the PKC delta gene is indicative of risk for a disorder characterized by abnormal or inadequate blood vessel formation.    
     
     
         12 . The method of  claim 11 , wherein presence of a the genetic lesions is evaluated by contacting the sample with a nucleic acid probe capable of hybridizing to PKC delta mRNA.  
     
     
         13 . A method of determining if a subject is at risk for a disorder characterized by abnormal or inadequate blood vessel formation, comprising: 
 determining the expression levels of the PKC delta in the sample of cells, wherein reduced expression of PKC delta as compared to levels of PKC delta expression in a normal subject is indicative of risk for a disorder characterized by abnormal or inadequate blood vessel formation.    
     
     
         14 . The method of  claim 13 , wherein expression of PKC delta is determined using an antibody capable of binding to the PKC delta protein.  
     
     
         15 . The method of  claim 13 , wherein expression of PKC delta is determined by detecting PKC delta mRNA levels.  
     
     
         16 . A method for identifying a compound capable of promoting angiogenesis, comprising: 
 contacting a cell capable of expressing a PKC delta polypeptide with a test compound; and determining the level of PKC delta polypeptide or nucleic acid expression, wherein a compound capable of increasing PKC delta polypeptide or nucleic acid expression is indicative of a compound capable of promoting angiogenesis.    
     
     
         17 . The method of  claim 16 , further comprising comparing the PKC delta polypeptide of nucleic acid expression levels with an identical cell which is not treated with the compound.  
     
     
         18 . A method for identifying a compound capable of inhibiting angiogenesis, comprising: 
 contacting a cell capable of expressing a PKC delta polypeptide with a test compound; and determining the level of PKC delta polypeptide or nucleic acid expression, wherein a compound capable of inhibiting PKC delta polypeptide or nucleic acid expression is indicative of a compound capable of inhibiting angiogenesis.